In vivo role of FLT3-CD45 signalling for bone remodelling

• Applicants: Professor Dr. Lorenz C. Hofbauer; Professor Dr. Jörg P. Müller; Professorin Dr. Martina Rauner
• Subject Area: Hematology, Oncology ; Cell Biology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 433256483

In the previous project period, the role of the oncogenic receptor tyrosine kinase (RTK) FLT3-ITD and protein tyrosine phosphatase CD45 in the regulation of osteogenesis was investigated using disease-specific mouse models. For this purpose, the bone phenotype of FLT3-ITD-expressing mice was characterized in detail, and the influence of FLT3-ITD and the inactivation of CD45 on bone cell activity and the signaling characteristics of the involved cell types was described. Thus, the project elucidated the previously unknown role of FLT3-ITD in the regulation of bone metabolism. These results provide further insight into normal and pathological bone physiology. It provides the potential for the targeted influencing of bone diseases to establish improved therapeutic approaches. In addition to the ongoing project-specific work, we started investigations that address the role of wild-type FLT3 on bone formation using FLT3 knock out mice (available at the FLI Jena) and the established experimental repertoire for the analysis of osteogenesis. Our preliminary work clearly shows a previously unnoticed function of FLT3-WT in the formation of the osteo-hematopoietic niche. Besides, we characterized the gene expression profiles of FLT3-ITD-positive versus FLT3-WT AML patients. Here we were able to show that the synthesis of oncogenic FLT3-ITD significantly alters the expression of a number of components involved in osteogenesis and their altered synthesis significantly controls the survival of FLT3-ITD-AML patients. In addition, our preliminary work has shown bone abnormalities occuring in AML patients that produce FTL3-ITD. The aims of the planned project extension are recruited from this preliminary work: i) The detailed characterization of the bone phenotype of mice inactivated for FLT3. The specific techniques are available in the laboratory of Applicants 2 and 3 specialized in bone biology. ii) Comparison of primary bone and cell material derived from FLT3-ITD with FLT3-WT-AML patients regarding bone microstructure, bone turnover and specific activity of cell types involved in bone turnover. Thus, this project extension will elucidate the mechanisms, how FLT3-mediated signaling pathways control bone formation and remodeling. The molecular characterization of the bone cell types involved, their stem cell biology, and repopulation capacity will describe the role of FLT3 in bone metabolism. Characterization of FLT3-ITD AML patient samples will provide insight, how this oncogene controls bone remodeling, the stem cell niche and the interaction of both in humans. Unraveling this mechanism is critical to understanding normal and pathological hematopoiesis and bone physiology, and provides the potential to target hematological and bone diseases to establish improved therapeutic approaches.

• DFG Programme: Research Grants